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Human Tim8a and Tim8b are paralogous intermembrane space proteins of the small TIM chaperone family. Yeast small TIMs function in the trafficking of proteins to the outer and inner mitochondrial membranes. This putative import function for hTim8a and hTim8b has been challenged in human models, but their precise molecular function(s) remains undefined. Likewise, the necessity for human cells to encode two Tim8 proteins and whether any potential redundancy exists is unclear. We demonstrate that hTim8a and hTim8b function in the assembly of cytochrome c oxidase (Complex IV). Using affinity enrichment mass spectrometry, we define the interaction network of hTim8a, hTim8b and hTim13, identifying subunits and assembly factors of the Complex IV COX2 module. hTim8‐deficient cells have a COX2 and COX3 module defect and exhibit an accumulation of the Complex IV S2 subcomplex. These data suggest that hTim8a and hTim8b function in assembly of Complex IV via interactions with intermediate‐assembly subcomplexes. We propose that hTim8–hTim13 complexes are auxiliary assembly factors involved in the formation of the Complex IV S3 subcomplex during assembly of mature Complex IV.

Infection with Plasmodium falciparum parasites results in approximately 627,000 deaths from malaria annually. Key to the parasite's success is their ability to invade and subsequently grow within human erythrocytes. Parasite proteins involved in parasite invasion and proliferation are therefore intrinsically of great interest, as targeting these proteins could provide novel means of therapeutic intervention. One such protein is P113 which has been reported to be both an invasion protein and an intracellular protein located within the parasitophorous vacuole (PV). The PV is delimited by a membrane (PVM) across which a plethora of parasite-specific proteins are exported via the Plasmodium Translocon of Exported proteins (PTEX) into the erythrocyte to enact various immune evasion functions. To better understand the role of P113 we isolated its binding partners from in vitro cultures of P. falciparum. We detected interactions with the protein export machinery (PTEX and exported protein-interacting complex) and a variety of proteins that either transit through the PV or reside on the parasite plasma membrane. Genetic knockdown or partial deletion of P113 did not significantly reduce parasite growth or protein export but did disrupt the morphology of the PVM, suggesting that P113 may play a role in maintaining normal PVM architecture.

SignificanceMitochondria are double-membraned eukaryotic organelles that house the proteins required for generation of ATP, the energy currency of cells. ATP generation within mitochondria is performed by five multisubunit complexes (complexes I to V), the assembly of which is an intricate process. Mutations in subunits of these complexes, or the suite of proteins that help them assemble, lead to a severe multisystem condition called mitochondrial disease. We show that SFXN4, a protein that causes mitochondrial disease when mutated, assists with the assembly of complex I. This finding explains why mutations in SFXN4 cause mitochondrial disease and is surprising because SFXN4 belongs to a family of amino acid transporter proteins, suggesting that it has undergone a dramatic shift in function through evolution.

Modulation of the host cell is integral to the survival and replication of microbial pathogens. Several intracellular bacterial pathogens deliver bacterial proteins, termed "effector proteins" into the host cell during infection by sophisticated protein translocation systems, which manipulate cellular processes and functions. The functional contribution of individual effectors is poorly characterized, particularly in intracellular bacterial pathogens with large effector protein repertoires. Technical caveats have limited the capacity to study these proteins during a native infection, with many effector proteins having only been demonstrated to be translocated during over-expression of tagged versions. Here, we developed a novel strategy to examine effector proteins in the context of infection. We coupled a broad, unbiased proteomics-based screen with organelle purification to study the host-pathogen interactions occurring between the host cell mitochondrion and the Gram-negative, Q fever pathogen Coxiella burnetii. We identify four novel mitochondrially-targeted C. burnetii effector proteins, renamed Mitochondrial Coxiella effector protein (Mce) B to E. Examination of the subcellular localization of ectopically expressed proteins confirmed their mitochondrial localization, demonstrating the robustness of our approach. Subsequent biochemical analysis and affinity enrichment proteomics of one of these effector proteins, MceC, revealed the protein localizes to the inner membrane and can interact with components of the mitochondrial quality control machinery. Our study adapts high-sensitivity proteomics to study intracellular host-pathogen interactions, providing a robust strategy to examine the subcellular localization of effector proteins during native infection. This approach could be applied to a range of pathogens and host cell compartments to provide a rich map of effector dynamics throughout infection.

OBJECTIVE: Fixed ratio blood product administration may improve outcomes in trauma patients with massive blood loss. The present study aimed to describe the impact of a major haemorrhage protocol (MHP) on the ratio of blood products administered for paediatric major trauma. METHODS: Retrospective observational study in a state-designated paediatric major trauma centre in Melbourne, Australia. Children with major trauma who received blood products in the ED were identified from a hospital trauma registry. Blood product ratios before, during and after implementation of a hospital MHP were compared in consecutive 2 year blocks. RESULTS: Over a 6 year period, 767 major trauma patients were identified, of whom 47 received blood products in the ED and were included in the analysis; 14 pre-MHP implementation, 24 during-MHP implementation and nine post-MHP implementation. No patients received blood products at a ratio of 1:1:1 for red blood cells:fresh frozen plasma:platelets, respectively, during any time period. In this cohort of predominantly blunt trauma, blood products were infrequently administered in the ED because of the low prevalence of massive blood loss. Coagulopathy and hypofibrinogenaemia were commonly observed, nearly half of included patients were managed operatively and one quarter did not survive their injuries. CONCLUSION: The implementation of a MHP did not change the ratio of blood product administration in this cohort of patients because of the infrequency of massive blood loss. Future studies may focus on the impact of treating coagulopathy and hypofibrinogenaemia on patient-centred outcomes.

The majority of proteins localised to mitochondria are encoded by the nuclear genome, with approximately 1500 proteins imported into mammalian mitochondria. Dysfunction in this fundamental cellular process is linked to a variety of pathologies including neuropathies, cardiovascular disorders, myopathies, neurodegenerative diseases and cancer, demonstrating the importance of mitochondrial protein import machinery for cellular function. Correct import of proteins into mitochondria requires the co-ordinated activity of multimeric protein translocation and sorting machineries located in both the outer and inner mitochondrial membranes, directing the imported proteins to the destined mitochondrial compartment. This dynamic process maintains cellular homeostasis, and its dysregulation significantly affects cellular signalling pathways and metabolism. This review summarises current knowledge of the mammalian mitochondrial import machinery and the pathological consequences of mutation of its components. In addition, we will discuss the role of mitochondrial import in cancer, and our current understanding of the role of mitochondrial import in neurodegenerative diseases including Alzheimer's disease, Huntington's disease and Parkinson's disease.

Acylglycerol kinase (AGK) is a mitochondrial lipid kinase that contributes to protein biogenesis as a subunit of the TIM22 complex at the inner mitochondrial membrane. Mutations in AGK cause Sengers syndrome, an autosomal recessive condition characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, and lactic acidosis. We mapped the proteomic changes in Sengers patient fibroblasts and AGKKO cell lines to understand the effects of AGK dysfunction on mitochondria. This uncovered down-regulation of a number of proteins at the inner mitochondrial membrane, including many SLC25 carrier family proteins, which are predicted substrates of the complex. We also observed down-regulation of SFXN proteins, which contain five transmembrane domains, and show that they represent a novel class of TIM22 complex substrate. Perturbed biogenesis of SFXN proteins in cells lacking AGK reduces the proliferative capabilities of these cells in the absence of exogenous serine, suggesting that dysregulation of one-carbon metabolism is a molecular feature in the biology of Sengers syndrome.

A comprehensive understanding of the phenotype of persistent HIV-infected cells, transcriptionally active and/or transcriptionally inactive, is imperative for developing a cure. The relevance of cell-surface glycosylation to HIV persistence has never been explored. We characterize the relationship between cell-surface glycomic signatures and persistent HIV transcription in vivo. We find that the cell surface of CD4+ T cells actively transcribing HIV, despite suppressive therapy, harbors high levels of fucosylated carbohydrate ligands, including the cell extravasation mediator Sialyl-LewisX (SLeX), compared with HIV-infected transcriptionally inactive cells. These high levels of SLeX are induced by HIV transcription in vitro and are maintained after therapy in vivo. Cells with high-SLeX are enriched with markers associated with HIV susceptibility, signaling pathways that drive HIV transcription, and pathways involved in leukocyte extravasation. We describe a glycomic feature of HIV-infected transcriptionally active cells that not only differentiates them from their transcriptionally inactive counterparts but also may affect their trafficking abilities.

OBJECTIVE: Thoracic trauma is a leading cause of paediatric trauma deaths. Traumatic cardiac arrest, tension pneumothorax and massive haemothorax are life-threatening conditions requiring emergency and definitive pleural decompression. In adults, thoracostomy is increasingly preferred over needle thoracocentesis for emergency pleural decompression. The present study reports on the early experience of thoracostomy in children, to inform debate regarding the best approach for emergency pleural compression in paediatric trauma. METHODS: Retrospective review of Ambulance Victoria and The Royal Children's Hospital Melbourne, Trauma Registry between August 2016 and February 2019 to identify children undergoing thoracostomy for trauma, either pre-hospital or in the ED. RESULTS: Fourteen children aged 1.2-15 years underwent 23 thoracostomy procedures over the 31 month period. The majority of patients sustained transport-related injuries, and underwent thoracostomies for the primary indications of hypoxia and hypotension. Two children were in traumatic cardiac arrest. Ten children underwent needle thoracocentesis prior to thoracostomy, but all required thoracostomy to achieve the necessary definitive decompression. All patients were severely injured with multiple-associated serious injuries and median Injury Severity Score 35.5 (17-75), three of whom died from their injuries. Thoracostomy in our cohort had a low complication rate. CONCLUSION: In severely injured children, thoracostomy is an effective and reliable method to achieve emergency pleural decompression, including in the young child. The technical challenges presented by children are real, but can be addressed by training to support a low complication rate. We recommend thoracostomy over needle thoracocentesis as the first-line intervention in children with traumatic cardiac arrest, tension pneumothorax and massive haemothorax. [Correction added on 23 September 2019 after first online publication: in the second sent

The gastrointestinal mucosa is critical for maintaining the integrity and functions of the gut. Disruption of this barrier is a hallmark and a risk factor for many intestinal and chronic inflammatory diseases. Inflammatory bowel disease (IBD) and HIV infection are characterized by microbial translocation and systemic inflammation. Despite the clinical overlaps between HIV and IBD, significant differences exist such as the severity of gut damage and mechanisms of immune cell homeostasis. Studies have supported the role of metabolic activation of immune cells in promoting chronic inflammation in HIV and IBD. This inflammatory response persists in HIV+ persons even after long-term virologic suppression by antiretroviral therapy (ART). Here, we review gut dysfunction and microbiota changes during HIV infection and IBD, and discuss how this may induce metabolic reprogramming of monocytes, macrophages and T cells to impact disease outcomes. Drawing from parallels with IBD, we highlight how factors such as lipopolysaccharides, residual viral replication, and extracellular vesicles activate biochemical pathways that regulate immunometabolic processes essential for HIV persistence and non-AIDS metabolic comorbidities. This review highlights new mechanisms and support for the use of immunometabolic-based therapeutics towards HIV remission/cure, and treatment of metabolic diseases.

Monocytes in humans consist of 3 subsets; CD14+CD16- (classical), CD14+CD16+ (intermediate) and CD14dimCD16+ (non-classical), which exhibit distinct and heterogeneous responses to activation. During acute inflammation CD14+CD16- monocytes are significantly elevated and migrate to the sites of injury via the adhesion cascade. The field of immunometabolism has begun to elucidate the importance of the engagement of specific metabolic pathways in immune cell function. Yet, little is known about monocyte metabolism and the role of metabolism in mediating monocyte activation and adherence to vessels. Accordingly, we aimed to determine whether manipulating the metabolism of CD14+CD16- monocytes alters their ability to become activated and adhere. We discovered that LPS stimulation increased the rate of glycolysis in human CD14+CD16- monocytes. Inhibition of glycolysis with 2-deoxy-D-glucose blunted LPS-induced activation and adhesion of monocytes. Mechanistically, we found that increased glycolysis was regulated by mTOR-induced glucose transporter (GLUT)-1. Furthermore, enhanced glycolysis increased accumulation of reactive oxygen species (ROS) and activation of p38 MAPK, which lead to activation and adhesion of monocytes. These findings reveal that glycolytic metabolism is critical for the activation of CD14+CD16- monocytes and contributes to our understanding of the interplay between metabolic substrate preference and immune cell function.

The evaluation of glucose metabolic activity in immune cells is becoming an increasingly standard task in immunological research. In this study, we described a sensitive, inexpensive, and non-radioactive assay for the direct and rapid measurement of the metabolic activity of CD4+ T cells in culture. A portable, custom-built Cell Culture Metabolite Biosensor device was designed to measure the levels of acidification (a proxy for glycolysis) in cell-free CD4+ T cell culture media. In this assay, ex vivo activated CD4+ T cells were incubated in culture medium and mini electrodes were placed inside the cell free culture filtrates in 96-well plates. Using this technique, the inhibitors of glycolysis were shown to suppress acidification of the cell culture media, a response similar to that observed using a gold standard lactate assay kit. Our findings show that this innovative biosensor technology has potential for applications in metabolic research, where acquisition of sufficient cellular material for ex vivo analyses presents a substantial challenge.

Human Tim8a and Tim8b are members of an intermembrane space chaperone network, known as the small TIM family. Mutations in TIMM8A cause a neurodegenerative disease, Mohr-Tranebjærg syndrome (MTS), which is characterised by sensorineural hearing loss, dystonia and blindness. Nothing is known about the function of hTim8a in neuronal cells or how mutation of this protein leads to a neurodegenerative disease. We show that hTim8a is required for the assembly of Complex IV in neurons, which is mediated through a transient interaction with Complex IV assembly factors, in particular the copper chaperone COX17. Complex IV assembly defects resulting from loss of hTim8a leads to oxidative stress and changes to key apoptotic regulators, including cytochrome c, which primes cells for death. Alleviation of oxidative stress with Vitamin E treatment rescues cells from apoptotic vulnerability. We hypothesise that enhanced sensitivity of neuronal cells to apoptosis is the underlying mechanism of MTS.

It is now clear that access to specific metabolic programmes controls the survival and function of various immune cell populations, including T cells. Efficient naïve and memory T cell homoeostasis requires the use of specific metabolic pathways and differentiation requires rapid and dramatic metabolic remodelling. While we are beginning to appreciate the crucial role of metabolic programming during normal T cell physiology, many of the potential impacts of ageing on metabolic homoeostasis and remodelling in T cells remain unexplored. This review will outline our current understanding of T cell metabolism and explore age-related metabolic changes that are postulated or have been demonstrated to impact T cell function.

Plasmodium falciparum, which causes malaria, extensively remodels its human host cells, particularly erythrocytes. Remodelling is essential for parasite survival by helping to avoid host immunity and assisting in the uptake of plasma nutrients to fuel rapid growth. Host cell renovation is carried out by hundreds of parasite effector proteins that are exported into the erythrocyte across an enveloping parasitophorous vacuole membrane (PVM). The Plasmodium translocon for exported (PTEX) proteins is thought to span the PVM and provide a channel that unfolds and extrudes proteins across the PVM into the erythrocyte. We show that exported reporter proteins containing mouse dihydrofolate reductase domains that inducibly resist unfolding become trapped at the parasite surface partly colocalizing with PTEX. When cargo is trapped, loop-like extensions appear at the PVM containing both trapped cargo and PTEX protein EXP2, but not additional components HSP101 and PTEX150. Following removal of the block-inducing compound, export of reporter proteins only partly recovers possibly because much of the trapped cargo is spatially segregated in the loop regions away from PTEX. This suggests that parasites have the means to isolate unfoldable cargo proteins from PTEX-containing export zones to avert disruption of protein export that would reduce parasite growth.

Untreated HIV infection is associated with progressive CD4+ T cell depletion, which is generally recovered with combination antiretroviral therapy (cART). However, a significant proportion of cART-treated individuals have poor CD4+ T cell reconstitution. We investigated associations between HIV disease progression and CD4+ T cell glucose transporter-1 (Glut1) expression. We also investigated the association between these variables and specific single nucleotide polymorphisms (SNPs) within the Glut1 regulatory gene AKT (rs1130214, rs2494732, rs1130233, and rs3730358) and in the Glut1-expressing gene SLC2A1 (rs1385129 and rs841853) and antisense RNA 1 region SLC2A1-AS1 (rs710218). High CD4+Glut1+ T cell percentage is associated with rapid CD4+ T cell decline in HIV-positive treatment-naïve individuals and poor T cell recovery in HIV-positive individuals on cART. Evidence suggests that poor CD4+ T cell recovery in treated HIV-positive individuals is linked to the homozygous genotype (GG) associated with SLC2A1 SNP rs1385129 when compared to those with a recessive allele (GA/AA) (odds ratio = 4.67; P = 0.04). Furthermore, poor response to therapy is less likely among Australian participants when compared against American participants (odds ratio: 0.12; P = 0.01) despite there being no difference in prevalence of a specific genotype for any of the SNPs analyzed between nationalities. Finally, CD4+Glut1+ T cell percentage is elevated among those with a homozygous dominant genotype for SNPs rs1385129 (GG) and rs710218 (AA) when compared to those with a recessive allele (GA/AA and AT/TT respectively) (P < 0.04). The heterozygous genotype associated with AKT SNP 1130214 (GT) had a higher CD4+Glut1+ T cell percentage when compared to the dominant homozygous genotype (GG) (P = 0.0068). The frequency of circulating CD4+Glut1+ T cells and the rs1385129 SLC2A1 SNP may predict the rate of HIV disease progression and CD4+ T cell recovery in untreated and treated infection, respecti

An emerging paradigm in immunology suggests that metabolic reprogramming and immune cell activation and functions are intricately linked. Viral infections, such as HIV infection, as well as cancer force immune cells to undergo major metabolic challenges. Cells must divert energy resources in order to mount an effective immune response. However, the fact that immune cells adopt specific metabolic programs to provide host defense against intracellular pathogens and how this metabolic shift impacts immune cell functions and the natural course of diseases have only recently been appreciated. A clearer insight into how these processes are inter-related will affect our understanding of several fundamental aspects of HIV persistence. Even in patients with long-term use of anti-retroviral therapies, HIV infection persists and continues to cause chronic immune activation and inflammation, ongoing and cumulative damage to multiple organs systems, and a reduction in life expectancy. HIV-associated fundamental changes to the metabolic machinery of the immune system can promote a state of "inflammaging", a chronic, low-grade inflammation with specific immune changes that characterize aging, and can also contribute to the persistence of HIV in its reservoirs. In this commentary, we will bring into focus evolving concepts on how HIV modulates the metabolic machinery of immune cells in order to persist in reservoirs and how metabolic reprogramming facilitates a chronic state of inflammation that underlies the development of age-related comorbidities. We will discuss how immunometabolism is facilitating the changing paradigms in HIV cure research and outline the novel therapeutic opportunities for preventing inflammaging and premature development of age-related conditions in HIV + individuals.

High Glut1 surface expression is associated with increased glycolytic activity in activated CD4+ T cells, the key targets of HIV. PI3K activation measured by p-Akt and OX40 is significantly elevated in CD4+Glut1+ T cells from HIV+ subjects. TCR engagement of CD4+Glut1+ cells from HIV+ subjects demonstrated hyper-responsive PI3K-mTOR signalling. High basal expression of Glut1 and OX40 on CD4+ T cells from cART-treated HIV+ patients represents a sufficiently metabolically active state that is permissive for HIV infection in vitro without external stimuli. However, since the vast majority of CD4+OX40+ T cells also express Glut1, OX40 expression rather than Glut1 itself may be associated with a metabolic state that facilitate HIV infection. Furthermore, infection of CD4+ T cells is limited by p110γ PI3K isoform inhibition. Modulating glucose metabolism may accordingly be useful to limit cellular activation and prevent residual HIV replication in ‘virologically suppressed’ anti-retroviral-treated HIV+ persons.

The realization that an intricate link exists between the metabolic state of immune cells and the nature of the elicited immune responses has brought a dramatic evolution to the field of immunology. We will focus on how metabolic reprogramming through the use of glycolysis and fatty-acid oxidation (sugar or fat) regulates the capacity of immune cells to mount robust and effective immune responses. We will also discuss how fine-tuning sugar and fat metabolism may be exploited as a novel immunotherapeutic strategy to fight viral infections or improve vaccine efficacy.

Metabolic remodeling occurs in immune cells during an infection. Host cells must upregulate energy production for growth, proliferation, and effector functions to limit the damage imposed by pathogens. One example, the hepatitis B virus, induces hepatic injury in human hepatocytes through dysregulation of aerobic glycolysis and lipid metabolism. Increased glycolytic metabolism mediated by elevated expression of Glut1, glucose influx, and lactate secretion is associated with this Warburg phenotype, a classic metabolic signature also observed in cancer cells. This article brings into focus the tight interaction between HBV infection and metabolic dysfunction and how these processes facilitate the progression of end-stage liver diseases, such as hepatocellular carcinoma. We also provide evidence and models by which other viruses such as HIV and Zika disrupt their host metabolic machinery. The emergence of the immunometabolism field provides novel opportunities to take advantage of intermediary metabolites and key metabolic pathways for diagnostic and therapeutic purposes.

Activation of the immune system occurs in response to the recognition of foreign antigens and receipt of optimal stimulatory signals by immune cells, a process that requires energy. Energy is also needed to support cellular growth, differentiation, proliferation, and effector functions of immune cells. In HIV-infected individuals, persistent viral replication, together with inflammatory stimuli contributes to chronic immune activation and oxidative stress. These conditions remain even in subjects with sustained virologic suppression on antiretroviral therapy. Here we highlight recent studies demonstrating the importance of metabolic pathways, particularly those involving glucose metabolism, in differentiation and maintenance of the activation states of T cells and monocytes. We also discuss how changes in the metabolic status of these cells may contribute to ongoing immune activation and inflammation in HIV- infected persons and how this may contribute to disease progression, establishment and persistence of the HIV reservoir, and the development of co-morbidities. We provide evidence that other viruses such as Epstein-Barr and Flu virus also disrupt the metabolic machinery of their host cells. Finally, we discuss how redox signaling mediated by oxidative stress may regulate metabolic responses in T cells and monocytes during HIV infection.

Mitochondrial fission is important for organelle transport, inheritance, and turnover, and alterations in fission are seen in neurological disease. In mammals, mitochondrial fission is executed by dynamin-related protein 1 (Drp1), a cytosolic guanosine triphosphatase that polymerizes and constricts the organelle. Recruitment of Drp1 to mitochondria involves receptors including Mff, MiD49, and MiD51. MiD49/51 form foci at mitochondrial constriction sites and coassemble with Drp1 to drive fission. Here, we solved the crystal structure of the cytosolic domain of human MiD51, which adopts a nucleotidyltransferase fold. Although MiD51 lacks catalytic residues for transferase activity, it specifically binds guanosine diphosphate and adenosine diphosphate. MiD51 mutants unable to bind nucleotides were still able to recruit Drp1. Disruption of an additional region in MiD51 that is not part of the nucleotidyltransferase fold blocked Drp1 recruitment and assembly of MiD51 into foci. MiD51 foci are also dependent on the presence of Drp1, and after scission they are distributed to daughter organelles, supporting the involvement of MiD51 in the fission apparatus.

OBJECTIVES: Glucose metabolism plays a fundamental role in supporting the growth, proliferation and effector functions of T cells. We investigated the impact of HIV infection on key processes that regulate glucose uptake and metabolism in primary CD4 and CD8 T cells. DESIGN AND METHODS: Thirty-eight HIV-infected treatment-naive, 35 HIV+/combination antiretroviral therapy, seven HIV+ long-term nonprogressors and 25 HIV control individuals were studied. Basal markers of glycolysis [e.g. glucose transporter-1 (Glut1) expression, glucose uptake, intracellular glucose-6-phosphate, and L-lactate] were measured in T cells. The cellular markers of immune activation, CD38 and HLA-DR, were measured by flow cytometry. RESULTS: The surface expression of the Glut1 is up-regulated in CD4 T cells in HIV-infected patients compared with uninfected controls. The percentage of circulating CD4Glut1 T cells was significantly increased in HIV-infected patients and was not restored to normal levels following combination antiretroviral therapy. Basal markers of glycolysis were significantly higher in CD4Glut1 T cells compared to CD4Glut1 T cells. The proportion of CD4Glut1 T cells correlated positively with the expression of the cellular activation marker, HLA-DR, on total CD4 T cells, but inversely with the absolute CD4 T-cell count irrespective of HIV treatment status. CONCLUSION: Our data suggest that Glut1 is a potentially novel and functional marker of CD4 T-cell activation during HIV infection. In addition, Glut1 expression on CD4 T cells may be exploited as a prognostic marker for CD4 T-cell loss during HIV disease progression.

Combined antiretroviral therapy (cART) extends the lifespan and the quality of life for HIV-infected persons but does not completely eliminate chronic immune activation and inflammation. The low level of chronic immune activation persisting during cART-treated HIV infection is associated with the development of diseases which usually occur in the elderly. Although T-cell activation has been extensively examined in the context of cART-treated HIV infection, monocyte activation is only beginning to be recognized as an important source of inflammation in this context. Here we examine markers and sources of monocyte activation during cART-treated HIV infection and discuss the role of monocytes during cardiovascular disease, HIV-associated neurocognitive disorder, and innate immune aging.

BACKGROUND: Aging is associated with immune dysfunction and the related development of conditions with an inflammatory pathogenesis. Some of these immune changes are also observed in HIV infection, but the interaction between immune changes with aging and HIV infection are unknown. Whilst sex differences in innate immunity are recognized, little research into innate immune aging has been performed on women. METHODS: This cross-sectional study of HIV positive and negative women used whole blood flow cytometric analysis to characterize monocyte and CD8(+) T cell subsets. Plasma markers of innate immune activation were measured using standard ELISA-based assays. RESULTS: HIV positive women exhibited elevated plasma levels of the innate immune activation markers CXCL10 (p<0.001), soluble CD163 (sCD163, p = 0.001), sCD14 (p = 0.022), neopterin (p = 0.029) and an increased proportion of CD16(+) monocytes (p = 0.009) compared to uninfected controls. Levels of the innate immune aging biomarkers sCD163 and the proportion of CD16(+) monocytes were equivalent to those observed in HIV negative women aged 14.5 and 10.6 years older, respectively. CXCL10 increased with age at an accelerated rate in HIV positive women (p = 0.002) suggesting a synergistic effect between HIV and aging on innate immune activation. Multivariable modeling indicated that age-related increases in innate immune biomarkers CXCL10 and sCD163 are independent of senescent changes in CD8(+) T lymphocytes. CONCLUSIONS: Quantifying the impact of HIV on immune aging reveals that HIV infection in women confers the equivalent of a 10-14 year increase in the levels of innate immune aging markers. These changes may contribute to the increased risk of inflammatory age-related diseases in HIV positive women.

BACKGROUND: Trauma systems should consistently monitor a given trauma population over a period of time. The Abbreviated Injury Scale (AIS) and derived scores such as the Injury Severity Score (ISS) are commonly used to quantify injury severities in trauma registries. To reflect contemporary trauma management and treatment, the most recent version of the AIS (AIS08) contains many codes which differ in severity from their equivalents in the earlier 1998 version (AIS98). Consequently, the adoption of AIS08 may impede comparisons between data coded using different AIS versions. It may also affect the number of patients classified as major trauma. METHODS: The entire AIS98-coded injury dataset of a large population based trauma registry was retrieved and mapped to AIS08 using the currently available AIS98-AIS08 dictionary map. The percentage of codes which had increased or decreased in severity, or could not be mapped, was examined in conjunction with the effect of these changes to the calculated ISS. The potential for free text information accompanying AIS coding to improve the quality of AIS mapping was explored. RESULTS: A total of 128280 AIS98-coded injuries were evaluated in 32134 patients, 15471 patients of whom were classified as major trauma. Although only 4.5% of dictionary codes decreased in severity from AIS98 to AIS08, this represented almost 13% of injuries in the registry. In 4.9% of patients, no injuries could be mapped. ISS was potentially unreliable in one-third of patients, as they had at least one AIS98 code which could not be mapped. Using AIS08, the number of patients classified as major trauma decreased by between 17.3% and 30.3%. Evaluation of free text descriptions for some injuries demonstrated the potential to improve mapping between AIS versions. CONCLUSIONS: Converting AIS98-coded data to AIS08 results in a significant decrease in the number of patients classified as major trauma. Many AIS98 codes are missing from the existing AIS map, and acr

INTRODUCTION: Many trauma registries have used the Abbreviated Injury Scale 1990 Revision Update 98 (AIS98) to classify injuries. In the current AIS version (Abbreviated Injury Scale 2005 Update 2008 - AIS08), injury classification and specificity differ substantially from AIS98, and the mapping tools provided in the AIS08 dictionary are incomplete. As a result, data from different AIS versions cannot currently be compared. The aim of this study was to develop an additional AIS98 to AIS08 mapping tool to complement the current AIS dictionary map, and then to evaluate the completed map (produced by combining these two maps) using double-coded data. The value of additional information provided by free text descriptions accompanying assigned codes was also assessed. METHODS: Using a modified Delphi process, a panel of expert AIS coders established plausible AIS08 equivalents for the 153 AIS98 codes which currently have no AIS08 map. A series of major trauma patients whose injuries had been double-coded in AIS98 and AIS08 was used to assess the maps; both of the AIS datasets had already been mapped to another AIS version using the AIS dictionary maps. Following application of the completed (enhanced) map with or without free text evaluation, up to six AIS codes were available for each injury. Datasets were assessed for agreement in injury severity measures, and the relative performances of the maps in accurately describing the trauma population were evaluated. RESULTS: The double-coded injuries sustained by 109 patients were used to assess the maps. For data conversion from AIS98, both the enhanced map and the enhanced map with free text description resulted in higher levels of accuracy and agreement with directly coded AIS08 data than the currently available dictionary map. Paired comparisons demonstrated significant differences between direct coding and the dictionary maps, but not with either of the enhanced maps. CONCLUSIONS: The newly-developed AIS98 to AIS08 compl